Nearly 60% of all adult patients and more than 75% of all pediatric patients with AIDS will suffer cognitive dysfunction ranging from memory loss and delirium to global dementia. The paradox is that despite profound cognitive impairment autopsy findings often show little change in neurons. For the most part, HIV-1 infects a specific class of brain cells, the CD4(+) mononuclear phagocytes which consist of reactive microglia and invading macrophages. Because neurons are rarely infected, the mechanisms to account for AIDS encephalopathy are unknown. Using an in vitro assay system, we have found that HIV-1-infected human mononuclear phagocytes, but not lymphocytes, release neurotoxins. Moreover, biochemical analyses suggest that these neurotoxins are a class of compounds unlike any known cytokine or cytotoxin secreted by microglia or macrophages. We will extend these important observations by identifying classes of HIV-1-infected cells that secrete neurotoxins and by determining the composition of secreted toxins. Neuron survival assays using chick embryo and fetal rat cells as target neurons will be used to monitor neuron killing activity produced by HIV-1-infected human test cells including various monocytoid or lymphoid cell lines as well as primary human monocytes and lymphocytes from AIDS and normal blood donors. Neurotoxins secreted by HIV-1 infected cell lines or peripheral blood mononuclear cells will be concentrated by ion exchange chromatography and isolated using conventional HPLC chromatographic techniques. Purified toxins will be infused into the brain of rat to assess in vivo effects. And finally, a series of experiments will examine mechanisms to activate cellular production of neurotoxins as well as to test the effectiveness of anti-viral drugs to inhibit production of neurotoxins. Uncovering specific cellular and molecular mechanisms of HIV-1-associated neurotoxicity may lead to new strategies for treatment of AIDS dementia.